Kristl G Claeys1,2, Angela Abicht3, Martin Häusler4, Stephanie Kleinle3, Martin Wiesmann5, Jörg B Schulz6, Rita Horvath7, Joachim Weis8. 1. Institute of Neuropathology and Department of Neurology, RWTH Aachen University, Aachen, Germany. 2. Department of Neurology, University Hospitals Leuven and University of Leuven (KU Leuven), Herestraat 49, 3000, Leuven, Belgium. 3. Medical Genetics Centre, München, Germany. 4. Department of Pediatrics, Division of Neuropediatrics and Social Pediatrics, RWTH Aachen University, Aachen, Germany. 5. Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, Aachen, Germany. 6. Department of Neurology and Jülich Aachen Research Alliance-Translational Brain Medicine, RWTH Aachen University, Aachen, Germany. 7. Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK. 8. Institute of Neuropathology, RWTH Aachen University, Aachen, Germany.
Abstract
INTRODUCTION: Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) is caused by m.8993T>G/C mutations in the mitochondrial adenosine triphosphate synthase subunit 6 gene (MT-ATP6). Traditionally, heteroplasmy levels between 70% and 90% lead to NARP, and >90% result in Leigh syndrome. METHODS: In this study we report a 30-year-old man with NARP and m.8993T>G in MT-ATP6. RESULTS: Although the patient carried the mutation in homoplasmic state in blood with similarly high levels in urine (94%) and buccal swab (92%), he presented with NARP and not the expected, more severe Leigh phenotype. The mutation could not be detected in any of the 3 analyzed tissues of the mother, indicating a large genetic shift between mother and offspring. Nerve biopsy revealed peculiar endoneurial Schwann cell nuclear accumulations, clusters of concentrically arranged Schwann cells devoid of myelinated axons, and degenerated mitochondria. CONCLUSIONS: We emphasize the phenotypic variability of the m.8993T>G MT-ATP6 mutation and the need for caution in predictive counseling in such patients. Muscle Nerve 54: 328-333, 2016.
INTRODUCTION: Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) is caused by m.8993T>G/C mutations in the mitochondrial adenosine triphosphate synthase subunit 6 gene (MT-ATP6). Traditionally, heteroplasmy levels between 70% and 90% lead to NARP, and >90% result in Leigh syndrome. METHODS: In this study we report a 30-year-old man with NARP and m.8993T>G in MT-ATP6. RESULTS: Although the patient carried the mutation in homoplasmic state in blood with similarly high levels in urine (94%) and buccal swab (92%), he presented with NARP and not the expected, more severe Leigh phenotype. The mutation could not be detected in any of the 3 analyzed tissues of the mother, indicating a large genetic shift between mother and offspring. Nerve biopsy revealed peculiar endoneurial Schwann cell nuclear accumulations, clusters of concentrically arranged Schwann cells devoid of myelinated axons, and degenerated mitochondria. CONCLUSIONS: We emphasize the phenotypic variability of the m.8993T>G MT-ATP6 mutation and the need for caution in predictive counseling in such patients. Muscle Nerve 54: 328-333, 2016.
Authors: Juan Sebastian Martin-Saavedra; Sara Reis Teixeira; Cesar Augusto Pinheiro Ferreira Alves; Fabrício Guimarães Gonçalves; Luis Octavio Tierradentro-García; Martin Kidd; Colleen Muraresku; Amy Goldstein; Arastoo Vossough Journal: Cerebellum Date: 2021-05-30 Impact factor: 3.847